Preliminary data from MH-50165 and its Supplement suggest that combination Li/Dvpx results in[unreadable] [unreadable] marked antimanic effectiveness in rapid-cycling BPD, but modest antidepressant effects. Most of the non-response[unreadable] [unreadable] was attributable to treatment-resistant depression (73% and 62% resistant depression and 27% and 38% resistant[unreadable] [unreadable] hypomania/mania/mixed, respectively). We believe these data suggest that more broadly effective regimens are[unreadable] [unreadable] needed, e.g., the addition of a third agent with more potent antidepressant properties. To address this need, R21[unreadable] [unreadable] MH-62650 is supporting a modified random assignment, single-center, 6-month, double blind, balanced parallelgroup[unreadable] [unreadable] comparison of two regimens of combination therapy (lithium/divalproex/blinded lamotrigine versus[unreadable] [unreadable] lithium/divalproex/placebo) for the acute and continuation outpatient management of depression, hypomania, and[unreadable] [unreadable] mania in 90 patients presenting in an index episode of depression. Project #3 proposes to carry out a similarly[unreadable] [unreadable] designed study, but in patients who are currently comorbid with alcohol, cocaine, and/or cannabis[unreadable] [unreadable] abuse dependence. To date, there are no published randomized, controlled trials in adults with BPD who are[unreadable] [unreadable] currently abusing alcohol or drugs.[unreadable] [unreadable]